ICAD: Amyloid Treatments Reduce Tau Tangles

Action Points

Explain that two small studies found that targeting amyloid plaques in patients with Alzheimer's disease may also result in decreases in tau tangles.

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

HONOLULU -- Treatments that target amyloid plaques in Alzheimer's disease patients may also be useful for reducing tau tangles, according to two small studies presented here.

One study, a pooled analysis of two randomized trials in 46 Alzheimer's patients, found that bapineuzumab significantly reduced total and phospho-tau in cerebrospinal fluid compared with placebo after one year, according to Kaj Blennow, MD, PhD, of the University of Goteborg in Sweden, and colleagues.

In the other study, conducted among 38 people, the Alzheimer's vaccine known as AN1792 -- a trial of which was halted earlier in the decade due to brain swelling -- was associated with reduced tau deposits in the cerebral cortex and hippocampus, Delphine Boche, MD, of the University of Southampton in England, and colleagues reported.

Both groups presented their findings at the International Conference on Alzheimer's disease in Honolulu.

"What these two studies have in common is that they demonstrate if you limit amyloid accumulation, it affects tau accumulation as well," William Thies, PhD, the chief medical and scientific officer for the Alzheimer's Association, told MedPage Today.

But he cautioned that he's "not sure it tells us much of anything new about the role of tau in Alzheimer's disease."

The primary therapeutic target in Alzheimer's disease has been the amyloid-beta peptide, the major constituent of plaques, but attention has recently been turned to the tau protein, which forms tangles in the brains of Alzheimer's patients.

It may be that amyloid changes happen early in the disease and tau-related changes happen downstream, where they have a more direct effect on cognitive function, Thies said.

Still, it's unclear whether the plaques or tangles play a larger role in causing Alzheimer's.

To test whether agents that target amyloid plaques also have an effect on tau, Boche and colleagues assessed 10 Alzheimer's patients who had been immunized with AN1792, an investigational amyloid-beta peptide.

In 2002, a phase II trial of this vaccine was halted because 6% of patients on the drug developed serious brain inflammation symptoms resembling meningoencephalitis. However, some of the patients continued to be followed.

Boche and colleagues compared the 10 patients they followed with 28 Alzheimer's patients who were not vaccinated.

They used immunostaining to assess amyloid-beta and phospho-tau in regions of cerebral grey matter that are affected by Alzheimer's pathology, including the superior and middle temporal gyrus, the medial frontal gyrus and inferior parietal lobule, the entorhinal cortex, the subiculum, and the CA1 hippocampus.

In the cerebral cortex, the researchers found significant reductions in both amyloid-beta and phospho-tau proteins among patients who had been immunized compared with placebo (5.25% versus 1.42%, P=0.001 and 1.08% versus 0.72%, P=0.048, respectively).

Boche said similar changes were observed in the hippocampus as well.

"This confirms the link between these two proteins," Boche told MedPage Today. "But we know as well that the vaccine patients didn't improve clinically."

The researchers also found that reductions in phospho-tau were confined to neuronal processes such as neuropil threads and dystrophic neurites. However, there was no accumulation in neuronal cell bodies, which contribute to neurofibrillary tangles.

In another study presented here, Blennow and colleagues found that bapineuzumab may decrease levels of phospho-tau in cerebrospinal fluid.

In this study, which pooled data from two small phase II randomized, multicenter, double-blind, controlled trials, the researchers looked at a total of 46 patients who received either bapineuzumab or a placebo.

One trial enrolled 35 patients; the other, 11 patients. Cerebrospinal fluid was collected at baseline and two weeks after the year-long trial.

In the larger trial, Blennow and colleagues found a trend towards a decrease in cerebrospinal fluid levels of phospho-tau in bapineuzumab group compared with placebo. There were no treatment effects in the smaller trial, but in a pooled analysis of both trials, there was a significant decrease in phospho-tau in the drug group compared with placebo (P=0.027).

Also in the pooled analysis, there was also trend toward a decrease in total tau, but it wasn't significant, Blennow said in an interview with MedPage Today that was monitored by a press officer.

He concluded that immunotherapy treatment targeting amyloid-beta may alter neurodegenerative processes that occur later in the disease process and are more directly associated with loss of function.

Still, he cautioned that the study was small and the findings need to be confirmed in larger groups of patients.

Two other studies in mice presented at the conference assessed agents that target tau directly. Thies said that several studies on the efficacy of amyloid-targeting agents will finish, and researchers will have more specific information "about where to go next."

Thies expects that "in the long term, we will probably have both amyloid medications -- if they work -- and tau medications, if they work."

He added that if Alzheimer's "turns out like most other chronic diseases, there will be populations that will be well-treated by beta-amyloid ... and additional populations that not only need amyloid reductions, but tau reductions as well."

Boche said she had no conflicts of interest, but said that Elan provided the amyloid antibodies used in the study, as well as data from the previously halted trial.

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